US20220040192A1 - Immunoproteasome inhibitor formulations - Google Patents

Immunoproteasome inhibitor formulations Download PDF

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US20220040192A1
US20220040192A1 US17/281,404 US201917281404A US2022040192A1 US 20220040192 A1 US20220040192 A1 US 20220040192A1 US 201917281404 A US201917281404 A US 201917281404A US 2022040192 A1 US2022040192 A1 US 2022040192A1
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kzr
formulations
reconstituted
lyophilization
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Evan Lewis
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Kezar Life Sciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • proteasome-mediated degradation In eukaryotes, protein degradation is predominately mediated through the ubiquitin pathway in which proteins targeted for destruction are ligated to the 76 amino acid polypeptide ubiquitin. Once targeted, ubiquitinated proteins then serve as substrates for the 26S proteasome, a multicatalytic protease, which cleaves proteins into short peptides through the action of its three major proteolytic activities. While having a general function in intracellular protein turnover, proteasome-mediated degradation also plays a key role in many processes such as major histocompatibility complex (MHC) class I antigen presentation, apoptosis, cell growth regulation, NF- ⁇ B activation, antigen processing, and transduction of pro-inflammatory signals.
  • MHC major histocompatibility complex
  • FIG. 2B shows RP-HPLC analysis trends for various formulations after storage for 6 months at 25° C.
  • FIG. 2C shows RP-HPLC analysis trends for various formulations after storage for 6 months at 40° C.
  • the pharmaceutical formulation disclosed herein can comprise KZR-616 in any suitable form.
  • the KZR-616 is present as a free base.
  • the KZR-616 is present as a salt.
  • the KZR-616 is present as a salt form selected from maleate, fumarate, oxalate, malate, sulfate, methanesulfonate, 2-naphthalenesulfonate, phosphate, halide, tartrate, citrate, tosylate, propionate, benzoate, and a combination thereof.
  • the KZR-616 is present as a solvate, such as a hydrate.
  • the formulations described herein can comprise any concentration of KZR-616 or salt thereof, as measured prior to lyophilization.
  • concentrations of KZR-616 or salt thereof include about 10 mg/mL to about 500 mg/mL, or about 25 mg/mL to about 400 mg/mL, or about 50 mg/mL to about 400 mg/mL, or about 50 mg/mL to about 300 mg/mL, or about 60 mg/mL to about 275 mg/mL, or about 70 mg/mL to about 250 mg/mL, or about 80 mg/mL to about 225 mg/mL, or about 90 mg/mL to about 225 mg/mL, or about 100 mg/mL to about 200 mg/mL, or about 110 mg/mL to about 200 mg/mL, or about 120 mg/mL to about 200 mg/mL, or about 120 mg/mL to about 220 mg/mL, or about 120 mg/mL to about 190 mg/mL, or about 120 mg/mL to about 180
  • the pharmaceutical formulations disclosed herein can be prepared by, e.g., admixing the KZR-616 or a salt thereof and the sugar to form a solution.
  • the solution is an aqueous solution.
  • the solution can be lyophilized to form the lyophilized pharmaceutical formulation.
  • the method of preparing the pharmaceutical formulation can further comprise reconstituting the lyophilized formulation with a solvent to form a reconstituted formulation described herein.
  • the solvent used to form a reconstituted formulation can be any solvent suitable to one of skill in the art to reconstitute a lyophilized formulation, for example, the solvent can comprise water or aqueous 5% dextrose.
  • Another aspect of the disclosure provides a method of treating an immune-related disease in a subject by administering the reconstituted formulations as described herein.
  • the disease is psoriasis, dermatitis, systemic scleroderma, sclerosis, Crohn's disease, ulcerative colitis; respiratory distress syndrome, meningitis; encephalitis; uveitis; colitis; glomerulonephritis; eczema, asthma, chronic inflammation; atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis; systemic lupus erythematosus (SLE); diabetes mellitus; multiple sclerosis; Reynaud's syndrome; autoimmune thyroiditis; allergic encephalomyelitis; Sjogren's syndrome; juvenile onset diabetes; tuberculosis, sarcoidosis, polymyositis, granulomatosis, vasculitis; pernicious anemia (Addison's
  • the disorder is lupus, lupus nephritis, rheumatoid arthritis, diabetes, scleroderma, ankylosing spondylitis, psoriasis, multiple sclerosis, Hashimoto's disease, meningitis, or inflammatory bowel disease.
  • the disease is lupus nephritis or SLE.
  • Another aspect of the disclosure provides a method of treating inflammation in a subject by administering a reconstituted formulation as disclosed herein.
  • a lyophilized pharmaceutical formulation as described herein, is placed in a vial.
  • MQ water such as a milliliter
  • a timer is started to measure the amount of time for the lyophilized pharmaceutical formulation to reconstitute and/or completely dissolve. Every thirty seconds the vial with the MQ water and the lyophilized formulation is gently swirled until the reconstitution is completed.
  • the stability of KZR-616 in various formulation conditions was examined in this Lyophilization Formulation Development study.
  • the conditions investigated in this study included buffered (10 mM succinate) and unbuffered formulations with various excipients (L-Glycine, Mannitol, and Trehalose) at different pH values (3.9-4.2).
  • the stability of KZR-616 at 150 mg/mL in different formulations was examined under static storage conditions at refrigerated (5° C.), ambient (25° C.), and accelerated (40° C.) temperatures for up to 6 months. Over the course of this 6 month study, Reversed Phase HPLC (RP-HPLC) analysis was the main analytical method used for monitoring KZR-616 stability.
  • RP-HPLC Reversed Phase HPLC
  • Lyophilized cakes displayed consistent appearances over 6 months of storage at all storage temperatures. Some increase in yellow coloration in the lyophiles were observed over time, especially at 25° C. and 40° C. This yellow coloration was more apparent after reconstitution. Following reconstitution, all formulations were free of visible particles. Over 6 months of storage, formulation pH and KZR-616 concentration values remained comparable to values observed at time zero. Reconstitution times also remained consistent over 6 months of storage, at less than four minutes and thirty seconds.
  • the leading formulation for lyophilized 150 mg/mL KZR-616 was identified as a formulation containing 2% trehalose at pH 4.2 and no additional buffer.
  • the active pharmaceutical ingredient (API) examined in this study was KZR-616.
  • the material used for this study was comprised of the following:
  • DSC Sub-ambient differential scanning calorimetry
  • F3, F4, and F5 containing glycine, mannitol or trehalose, respectively.
  • the method program used is as follows: isothermal hold at ⁇ 60° C. for 1 minute and heat from ⁇ 60° C. to 25° C. at 5° C./minute.
  • F3, F4, and F5 showed glass transition temperatures (T g ) of ⁇ 16° C., ⁇ 15° C., and ⁇ 33° C., respectively, Table 1. Crystallization occurred for F4 with devitrification temperature (T d ) at ⁇ 10° C., therefore an annealing step was added to obtain more complete crystallization before primary drying. This data was implemented in the initial lyophilization cycle, Table 3.
  • KZR-616 maleate was dissolved in filtered Milli-Q® (MQ) water at a target concentration of 170 mg/mL, KZR-616 in MQ was then heated to 60° C. for approximately 2 minutes to dissolve the drug substance into solution.
  • Formulations were prepared as 10 ⁇ stocks, and spiked into aliquots of the DS/MQ solution at a ratio of 1:9 (Buffer: DS). Each formulation's pH was titrated to target pH with NaOH. Under aseptic conditions in the BSC, all samples were sterile-filtered through 0.2 ⁇ m filters and filled into 3 cc vials at a 1.0 mL fill volume.
  • the samples were partially stoppered with sterile stoppers, placed in the lyophilizer, and surrounded by empty vials.
  • the samples were lyophilized using the parameters detailed in Table 3. Following the initial lyophilization cycle, the samples were reconstituted with 1 mL of filtered MQ water and analyzed. Lyophilization Cycle Development formulations were prepared with respect to Table 2.
  • KZR-616 was dissolved in filtered MQ water at a target concentration of 170 mg/mL. KZR-616 in MQ was then heated to 60° C. for approximately 2 minutes to dissolve the drug substance into solution.
  • Formulations were prepared as 10 ⁇ stocks and spiked into aliquots of the DS/MQ solution at a ratio of 1:9 (Buffer: DS). Each formulation's pH was titrated to target pH with NaOH. Under aseptic conditions in the BSC, all samples were sterile-filtered through 0.2 ⁇ m filters and filled into 3 cc vials at a 1.0 mL fill volume.
  • the formulation matrix (buffer, bulking agent concentrations, pH) are outlined in Table 1.
  • the samples were partially stoppered with sterile stoppers, placed in the freeze dryer and surrounded by empty vials.
  • the samples were lyophilized using the parameters detailed in Table 4. Following lyophilization, the samples were reconstituted with 1 mL of filtered MQ water and analyzed following the methods outlined in Table 8.
  • KZR-616 was dissolved in filtered MQ water as a stock solution at a concentration of 170 mg/mL. KZR-616 stock solution was heated to 60° C. for approximately 2 minutes to completely dissolve the drug substance.
  • Formulation buffers were prepared as 10 ⁇ stock solutions. Each formulation was prepared with 10 ⁇ buffer stock solution, DS stock (170 mg/mL), and MQ to target the final concentration of 150 mg/mL. The pH of each formulation was adjusted to the target pH using NaOH. Under aseptic conditions in the BSC, all samples were sterile-filtered through 0.2 ⁇ m filters and filled into 3 cc vials at a 1.0 mL fill volume. The samples were partially stoppered with sterile stoppers, placed in the freeze dryer and surrounded by empty vials. The samples were lyophilized using the parameters detailed in Table 4.
  • KZR-0214142 and C15072369-FF1600 Two different drug substance lots (KZR-0214142 and C15072369-FF1600) of KZR-616 were individually dissolved in MQ to a concentration of 170 mg/mL and were heated to 60° C. for approximately 2 minutes to completely dissolve the drug substance. Both 170 mg/ml preparations were then diluted with 10 ⁇ target buffer (F5, 2% trehalose at pH 4.2) to 150 mg/ml. The pH of each formulation was titrated to the target pH using NaOH. Under aseptic conditions in the BSC, all samples were sterile-filtered through 0.2 ⁇ m filters and filled into 3 cc vials at a 1.0 mL fill volume. The samples were partially stoppered with sterile stoppers, placed in the freeze dryer, and surrounded by empty vials to prevent movement. The samples were lyophilized using the parameters detailed in Table 5.
  • extinction coefficient of 1.8495 (mg/mL)-1 cm-1 was determined by generating a standard curve (1 mg/mL, 0.75 mg/mL, 0.5 mg/mL, and 0.25 mg/mL, serially diluted in MQ).
  • KZR-616 was analyzed via a full wavelength scan and showed maximal absorbance at 272 nm. This wavelength was used to measure concentration.
  • FTIR Pre-lyophilization and post-lyophilization formulations were analyzed to determine the fingerprint of formulation containing bulking agents. (Performed post-lyophilization development cycle #1 and #2)
  • Reconstitution time Lyophilized formulations are reconstituted with one milliliter of filter water.
  • FT-IR Fastier-transform infrared spectroscopy
  • the osmolality of the nine (9) formulations was measured following sample preparation, prior to any stress exposure. Lyophilization cycle #1 formulations and specific reagents are outlined in Table 2. After confirming the osmolality of cycle #1 formulations (Table 12), the bulking agent concentrations were decreased for cycle #2, to target isotonic osmolality's ( ⁇ 300 Osmo). Lyophilization cycle #2 displayed isotonic osmolality measurements Pre-lyophilization and post reconstitution (Table 12).
  • Lyophilization Cycles 1 and 2 displayed comparable pH values Pre-lyophilization and after reconstitution (Table 13). However, after reconstitution Lyophilization Cycle #2 displayed pH values closer to target.
  • Lyophilization cycle #1 displayed reconstitution times of 4:31 minutes or less, while cycle #2 displayed reconstitution times of 4:12 minutes or less (Table 14).
  • the visual appearance of the lyophilized formulations displayed elegant cakes.
  • the lyophilized cakes displayed a slight yellowish tint, which increased in color with elevated temperatures.
  • Post reconstitution formulations were clear, free of particles, but also displayed a yellowish coloration.
  • formulations at 5° C. and 25° C. displayed comparable coloration to time zero.
  • formulations at 40° C. displayed a darker yellowish tint compared to time zero.
  • the osmolality of the nine (9) formulations was measured following sample preparation, prior to any stress exposure, shown on Table 20. Bulking agent concentrations were based on lyophilization cycle development #2 results, to target isotonic formulation at ⁇ 300 mOsm. Following 6 months, formulation F5 displayed comparable osmolality values to those observed at time zero.
  • formulations were reconstituted with one milliliter of filtered MQ.
  • a timer began to measure the amount of time each formulation required to homogenize.
  • formulations displayed comparable reconstitution times to time zero.
  • all formulations displayed reconstitution times less than three minutes and thirty seconds (Table 23).
  • Formulations F2 and F5 showed the highest main peak percentages and the slowest rate of degradation. Following six (6) months of incubation at 40° C., all formulations, with the exception of F8, retained main peak percentages of ⁇ 70.0%. Formulation F5 showed the highest main peak percentages and the slowest rate of degradation (80.3%).
  • formulations displayed comparable moisture content values to time zero (Table 31). All lyophilized formulations continued to show moisture content values less than 1%. The difference in secondary drying temperatures displayed a slight difference in moisture content; higher temperatures displayed the least moisture percentages.
  • Moisture Opt. Moisture Content Measurements (Time Zero) Sample Code % Moisture Content % Average 1% Water Std 0.92 10A #1 0.24 0.34 10A #2 0.40 10A #3 0.39 25A #1 0.36 0.32 25A #2 0.29 25A #3 0.30 35A #1 0.17 0.21 35A #2 0.20 35A #3 0.27 50A #1 0.20 0.19 50A #2 0.19 50A #3 0.18 25B #1 0.29 0.31 25B #2 0.33
  • the samples from Lot B showed larger decreases in main peak percentages compared to the corresponding Lot A samples, with a main peak percentage of 90.3%. This was due to large increases in KZR-0214142 that were observed in addition to the degradant peaks not observed in samples from Lot A.
  • the stability of KZR-616 in various formulation conditions was examined in this Lyophilization Formulation Development study.
  • the conditions investigated in this study included buffered (10 mM succinate) and unbuffered formulations with various bulking agents (L-Glycine, Mannitol, Trehalose) at different pH values (3.9-4.2).
  • the stability of KZR-616 in different formulations was examined under storage conditions at refrigerated (5° C.), ambient (25° C.), and accelerated (40° C.) temperatures for up to 6 months and was analyzed by Reversed Phase HPLC (RP-HPLC) to evaluate KZR-616 stability.
  • RP-HPLC Reversed Phase HPLC
  • the sample from lot 1605R110 showed larger decreases in main peak percentages compared to the corresponding lot 015072369-FF16001 sample, with a main peak percentage of 90.3%. This was due to large increases in KZR-0214142 that were observed in addition to the degradant peaks observed in samples from lot 015072369-FF16001. This study yielded comparable KZR-616 stability after 4 weeks and confirmed low moisture content values, with no significant moisture difference between lyophilization cycles. The difference in secondary drying temperatures displayed a slight difference in main peak stability at time zero. Following four weeks at 40° C., all formulated samples displayed comparable stability, suggesting that improved stability was not achieved with further drying of the cake.
  • trehalose-containing formulations F2 and F5 displayed the highest main peak percentages (78.7%, 80.3%) after 6 months at 40° C. This data suggests that KZR-616 is most stabilized in an unbuffered formulation at pH 4.2 in the presence of sugars. This is further supported by the trends of sugar-free formulations F3, F6, and F8 showing the poorest stability results.
  • Tables 34-36 show a comparison of the pharmacokinetics (“PK”) and toxicokinetics (“TK”) observed with different KZR-616 formulations in various animals.
  • the Test Formulation comprises various concentrations of KZR-616 as noted in 2 wt % trehalose at pH 4.2 upon dissolution with water for injection.
  • the Comparative Formulation comprises various concentrations of KZR-616 as noted in aqueous 10 wt % polysorbate-80 (“PS-80’).
  • Table 34 shows that the Test Formulation exhibited faster absorption and elimination as well as 2-3 fold higher C max compared to the Comparative formulation. Similar AUCs were observed for both formulations.
  • Table 35 shows faster absorption and elimination as well as 1.2-3.7 fold higher C max was observed for the Test formulation. A 0.7-1.7 fold difference in AUCs was observed for the two formulations.
  • Test Formulation of Table 36 was prepared as a water for injection (“WFI”) formulation described above and Comparative Formulation was prepared as an aqueous 10 wt % polysorbate-80 (“PS-80”) formulation. Faster absorption and elimination as well as 1.1-2.4 fold higher C max was observed for the Test formulation. A 0.6-1.0 fold difference in AUCs was observed for the two formulations.
  • WFI water for injection
  • PS-80 polysorbate-80

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JP6835710B2 (ja) * 2014-10-01 2021-02-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ ボロン酸誘導体
LT3478670T (lt) * 2016-06-29 2023-05-25 Kezar Life Sciences Kristalinės peptidų epoksiketono imunoproteasomų inhibitoriaus druskos

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